Towards gene therapy for IPEX syndrome

Borna, Simon; Lee, Esmond; Sato, Yohei; Bacchetta, Rosa

doi:10.1002/eji.202149210

Cited by 23 publications

(19 citation statements)

References 63 publications

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“…As a first step to address one of these issues, successful in vitro gene therapy of hyperactivated T cells has been shown with PBMCs from MUNC13‐4 deficient patients with active HLH (Dettmer et al , 2019 ). Additional innovative approaches are under development for gene repair/editing of autologous primary human T cells to solve these problems and to restore functionality as demonstrated for FHL‐2, FHL‐3, XLP, IPEX, and CD40L (Hubbard et al , 2016 ; Ghosh et al , 2018 ; Panchal et al , 2018 , 2021 ; Takushi et al , 2020 ; Borna et al , 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Adoptive T cell therapy cures mice from active hemophagocytic lymphohistiocytosis (HLH)

et al. 2022

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Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. First‐line therapeutic regimens directed against activated immune cells or secreted cytokines show limited efficacy since they do not target the underlying immunological problem: defective lymphocyte cytotoxicity causing prolonged immune stimulation. A potential rescue strategy would be the adoptive transfer of ex vivo gene‐corrected autologous T cells. However, transfusion of cytotoxicity‐competent T cells under conditions of hyperinflammation may cause more harm than benefit. As a proof‐of‐concept for adoptive T cell therapy (ATCT) under hyperinflammatory conditions, we transferred syngeneic, cytotoxicity‐competent T cells into mice with virally triggered active primary HLH. ATCT with functional syngeneic trigger‐specific T cells cured Jinx mice from active HLH without life‐threatening side effects and protected Perforin‐deficient mice from lethal HLH progression by reconstituting cytotoxicity. Cured mice were protected long‐term from HLH relapses. A threshold frequency of transferred T cells with functional differentiation was identified as a predictive biomarker for long‐term survival. This study is the first proof‐of‐concept for ATCT in active HLH.

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Section: Discussionmentioning

confidence: 99%

Adoptive T cell therapy cures mice from active hemophagocytic lymphohistiocytosis (HLH)

et al. 2022

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“…In our work, we focused on evaluating the Treg lineage commitment during development in the thymus in controls and 22q11.2DS patients, and thus we have not analyzed the function of 22q11 Treg, which represents a limitation of this work and warrants future in-depth analyses of 22q11.2DS thymic and peripheral Treg function. Autologous engineered Treg therapy obtained from converted CD4+ Tconv cells might be a suitable option for 22q11.2DS patients ( 27 ), as such cells could overcome 22q11.2DS developmental, or cell intrinsic Treg defects as well as defects caused by divergent TCR evolution associated with peripheral T cell expansion.…”

Section: Discussionmentioning

confidence: 99%

Analyses of thymocyte commitment to regulatory T cell lineage in thymus of healthy subjects and patients with 22q11.2 deletion syndrome

Borna

Dejene²,

Lakshmanan³

et al. 2023

Front. Immunol.

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The Chromosome 22q11.2 deletion syndrome (22q11.2DS) results in an inborn error of immunity due to defective thymic organogenesis. Immunological abnormalities in 22q11.2DS patients are thymic hypoplasia, reduced output of T lymphocytes by the thymus, immunodeficiency and increased incidence of autoimmunity. While the precise mechanism responsible for increased incidence of autoimmunity is not completely understood, a previous study suggested a defect in regulatory T cells (Treg) cell lineage commitment during T cell development in thymus. Here, we aimed to analyze this defect in more detail. Since Treg development in human is still ill-defined, we first analyzed where Treg lineage commitment occurs. We performed systematic epigenetic analyses of the Treg specific demethylation region (TSDR) of the FOXP3 gene in sorted thymocytes at different developmental stages. We defined CD3+CD4+CD8+ FOXP3+CD25+ as the T cell developmental stage in human where TSDR demethylation first occurs. Using this knowledge, we analyzed the intrathymic defect in Treg development in 22q11.2DS patients by combination of TSDR, CD3, CD4, CD8 locus epigenetics and multicolor flow cytometry. Our data showed no significant differences in Treg cell frequencies nor in their basic phenotype. Collectively, these data suggest that although 22q11.2DS patients present with reduced thymic size and T cell output, the frequencies and the phenotype of Treg cell at each developmental stage are surprisingly well preserved.

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“…For an overview of the various gene therapy approaches to treat IPEX, please see our recent review ( Borna et al, 2022b ) and the open clinical trial (NCT05241444). Here, we focus on the CRISPR/Cas9 gene editing approach in HSPC.…”

Section: Applying Dsb-based Genome Editing Technology For Correcting ...mentioning

confidence: 99%

Rare immune diseases paving the road for genome editing-based precision medicine

Pavel-Dinu¹,

Borna²,

Bacchetta

2023

Front. Genome Ed.

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Clustered regularly interspaced short palindromic repeats (CRISPR) genome editing platform heralds a new era of gene therapy. Innovative treatments for life-threatening monogenic diseases of the blood and immune system are transitioning from semi-random gene addition to precise modification of defective genes. As these therapies enter first-in-human clinical trials, their long-term safety and efficacy will inform the future generation of genome editing-based medicine. Here we discuss the significance of Inborn Errors of Immunity as disease prototypes for establishing and advancing precision medicine. We will review the feasibility of clustered regularly interspaced short palindromic repeats-based genome editing platforms to modify the DNA sequence of primary cells and describe two emerging genome editing approaches to treat RAG2 deficiency, a primary immunodeficiency, and FOXP3 deficiency, a primary immune regulatory disorder.

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Towards gene therapy for IPEX syndrome

Cited by 23 publications

References 63 publications

Adoptive T cell therapy cures mice from active hemophagocytic lymphohistiocytosis (HLH)

Adoptive T cell therapy cures mice from active hemophagocytic lymphohistiocytosis (HLH)

Analyses of thymocyte commitment to regulatory T cell lineage in thymus of healthy subjects and patients with 22q11.2 deletion syndrome

Rare immune diseases paving the road for genome editing-based precision medicine

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